Jan. 10, 2018
Lupus Research Alliance Announces New Grants for Translational Research
Seven Outstanding Investigators Chosen for Prestigious Lupus Research Grants
The Lupus Research Alliance is proud to announce the recipients of its Target Identification in Lupus (TIL) grants designed to move research discoveries quickly from the laboratory to the patient’s bedside. Seven outstanding scientists from across the United States will receive 3-year, up to $600,000 awards for innovative research projects expected to address fundamental questions in lupus research and remove barriers to new treatments and a possible cure for lupus and its complications.
With his TIL grant, Roberto Caricchio, MD, Temple University is studying whether usually harmless, common bacterial infections, such as urinary tract infections, might be an environmental trigger of lupus onset and flares in genetically at-risk individuals. Normally, a bacterial infection sets off the immune system to make antibodies and take other actions to fight off the invading bacteria. Dr. Caricchio’s theory is that in people who are susceptible to lupus, those infections also cause the immune system to make antibodies that recognize and attack a person’s own body.
Dr. Caricchio will look specifically at urinary tract infections (UTIs) in people with and without lupus. Some bacteria that cause UTIs produce a protein called “curli” that can bind to DNA and form a compound that triggers lupus in mouse models. Preliminary evidence shows that individuals with lupus have antibodies against this curli/DNA compound. Dr. Caricchio will investigate whether curli/DNA antibodies can predict lupus in at-risk people and if UTIs in people who have lupus create curli/DNA compounds in their blood that cause flares. This exciting research could open a new avenue of approaches to treat and even prevent lupus.
Lupus affects nine times more women than men. One explanation for this phenomenon lies in the difference between women’s and men’s chromosomes, the long pieces of DNA within each cell that contain our genes lined up one after the other like beads on a string. Women have two X chromosomes, while men have one X and one Y chromosome. Laura Carrel, PhD, The Pennsylvania State University College of Medicine is investigating how this difference in the number of X chromosomes might cause women to be more susceptible to lupus than men.
Normally, in a woman’s cells, the genes on one of her X chromosomes are active and those on the other are turned off or inactive. But Dr. Carrel has shown that in all women, about 10% of genes on the “inactive” X chromosome escape from the inactivation process and are actually active. She hypothesizes that the level of gene activity on the inactive chromosome might be even higher in women with lupus. To test this theory, Dr. Carrel will study the immune cells of women with and without lupus to find X chromosome genes that are more active in women with lupus. This research project will help us understanding the biology of lupus and point to new targets for drug discovery.
SAVI (STING-associated vasculopathy with onset in early infancy) is a disease caused by a mutation in the gene that makes a protein called STING. In patients with SAVI, the STING protein is locked in its “on” position, causing immune cells to be constantly active. These active immune cells create inflammation that damages tissues throughout the body in a manner that is similar in many respects to lupus. While lupus is caused by more complex genetic and environmental factors than SAVI, STING is known to also play a role in lupus. Katherine Fitzgerald, PhD, University of Massachusetts Medical School is exploring how the mutant STING protein goes rogue to trigger the lupus-like symptoms in SAVI patients. By focusing on the simpler model system of a single-gene disease like SAVI, Dr. Fitzgerald will gain new information about the STING pathway that can be applied to develop new treatment approaches to lupus.
Lupus nephritis (kidney disease) is one of the most serious complications of lupus. With the TIL grant support, Chandra Mohan, MD, PhD, University of Houston will build on his existing discoveries to evaluate a potential new therapeutic target for lupus nephritis. In comparing the levels of 1,100 proteins in the urine of lupus patients and healthy controls, Dr. Mohan already found several differences, and one in particular stood out. The protein ALCAM (activated leukocyte cell adhesion molecule) was consistently higher in those with lupus compared to the controls. ALCAM is a small molecule on the outside of T cells of the immune system that helps the T cells move through the tissues of the body, including the kidney. Dr. Mohan will now find out how ALCAM is involved in lupus nephritis and evaluate whether it is a good target for new drug development to prevent or treat the complication.
Scientists have found more than 50 regions of DNA that contribute to lupus risk. At least 35 of these DNA regions regulate gene activity—they serve as magnets that attract proteins, which in turn, act as control switches that determine whether a gene is more or less active. Variations in gene activity influence a person’s biology—for example, whether they are more or less likely to develop a disease like lupus. The TIL grant will enable Peter A. Nigrovic, MD, Brigham and Women’s Hospital to study each of these 35 DNA control centers to determine how they contribute to lupus risk.
Dr. Nigrovic will identify the proteins that interact with the DNA regions using state-of-the-art technologies. Once the control proteins are known, he will be able to build up a more complete picture of the genes and biological pathways that cause lupus. This line of research is expected to discover new targets for treatments to prevent or cure lupus.
Janos Peti-Peterdi, MD, PhD, University of Southern California studies what goes wrong with the kidneys in people with lupus and how kidneys damaged by lupus can be repaired. He has developed a pioneering research technique, known as “intravital imaging,” to use a highly sensitive microscope to directly examine in fine detail the kidneys in an animal model of lupus. He will also test two potential treatments for lupus nephritis and observe whether they are effective at repairing the kidneys by regenerating damaged cells. Using the insights and data gained as a springboard, Dr. Peti-Peterdi will then focus his research on patients with lupus nephritis to find ways to help their kidneys heal. This research project promises to improve treatment of lupus nephritis for the benefit of all patients with this serious complication.
Betty Tsao, PhD, Medical University of South Carolina found a mutation in a specific gene, NCF1, that predicts increased risk for several autoimmune diseases, including lupus. The mutation causes a reduction in the amount of reactive oxygen species (ROS), small chemicals that contain oxygen and other elements that are formed as a normal byproduct of the body’s metabolism. Hydrogen peroxide is one example of an ROS. Interestingly, ROS are normally thought of as troublemakers in the body, causing stress and tissue damage that contribute to many diseases, as well as signs of aging. To understand why a reduction in ROS might lead to lupus, Dr. Tsao will create an animal model with the mutated NCF1 gene. This model will allow her to understand how reduced ROS affects immune system cell function. Ultimately, Dr. Tsao expects to find new targets in the NCF1/ROS pathway for drug development to prevent or treat lupus.